TREM2 keeps myelinated axons under wraps

The polyanion-binding cell surface receptor TREM2 is expressed on myeloid cell populations, including microglia of the CNS. Individuals with inactivating mutations in TREM2 or TYROBP, which encodes the TREM2 adapter DAP12, develop Nasu-Hakola disease, a rare, lethal dementia that manifests in early adulthood and is characterized by demyelinating lesions. The link between loss of TREM2 function and dysfunctional myelination is not clear. Pietro Poliani, Yaming Wang, and colleagues at the University of Brescia School of Medicine used murine models to investigate a possible role for microglial TREM2 in myelin repair following injury. An age-dependent expansion of microglia was absent in the brains of mice lacking TREM2, and the microglia that were present were notably smaller and dystrophic. In a chronic toxin model of demyelination, loss of TREM2 severely impaired remyelination and removal of myelin debris during prolonged toxin exposure. Further, Trem2 deletion altered demyelination- and recovery-associated transcriptional responses, including a dysregulation of genes involved in phagocytosis, lipid transport, and inflammation. Evaluation of potential TREM2 ligands in GFP reporter cells revealed that various myelin-associated lipids activate TREM2 signaling. Together, the results of this study demonstrate that TREM2 is required for age-dependent microglia expansion and mediates remyelination following injury. The accompanying image shows representative microglia (stained with anti-Iba-1, brown) in two-year-old WT (left) and Trem2 knockout (right) mice. Note the dysmorphic appearance of microglia in the TREM2-deficient animals.